Acute renal failure (ARF) is the most common renal disease requiring hospitalization and is associated with significant mortality. It is increasingly recognized that ARF predisposes the kidney to long-term complications in surviving patients. We have previously shown evidence for peritubular capillary dropout following ARF and hypothesized that this is an important factor predisposing progressive renal disease. Work from the previous project period has shown that following recovery from ARF, Na-diet predisposes hypertension and hastens chronic kidney disease. While vascular dropout may contribute to this alteration in function, it is additionally hypothesized, in the current application that I/R-induced alterations in vascular reactivity and fibroblast deposition may also contribute to alterations in renal function leading to CRF.
Specific aim 1 will evaluate alterations in vascular reactivity and define the role of oxidant stress systems in the alterations of renal hemodynamics and sodium excretion. These studies will focus on the post-ischemic response to perfusion pressure, angiotensin II and determine the mechanism of protection by VEGF. The second specific aim will explore vascular dropout directly;the studies will evaluate the proliferative potential of endothelial progenitor cells in the kidney and evaluate the efficacy of endothelial progenitor cells (EPC) in restoring renal vascular function following injury, with and without angiogenic growth factor therapy. We will compare EPCs derived from either bone-marrow or from vessel walls, determine if the source of EPC affects long-term renal vascular function. Studies will determine if EPC cells incorporate to promote new blood vessel formation, affect renal blood flow under the influence of angiogenic growth factors, and evaluate long-term renal function and progression of CRF. The final specific aim (#3) is designed to define the relative impact of interstitial myofibroblast vs. blood vessel dropout on progression to CRF following ARF. These studies will utilize transgenic mice harboring fibroblast specific expression of the HSV thymidine kinase gene, to deplete (myo) fibroblasts following the induction of ARF. These studies are designed to separate the influence of interstitial cells vs. peritubular capillary loss in predisposing long term changes in renal function and hemodynamics.

Public Health Relevance

Acute renal failure (ARF) is the most common renal disease requiring hospitalization is associated with significant mortality. As the number of patients that survive ARF is increasing, it is becoming recognized that ARF predisposes secondary chronic kidney disease and hypertension. The work in this application will utilize rodent models of ARF that develop secondary chronic kidney disease. The overall goal is to gain an understanding as to how acute injury changes kidney structure and function so as to develop into chronic kidney disease. The acquisition of this information is required to design effective strategies for this increasingly apparent health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063114-09
Application #
8111975
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2003-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$353,912
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Physiology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Collett, Jason A; Traktuev, Dmitry O; Mehrotra, Purvi et al. (2017) Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury. J Cell Mol Med 21:1420-1430
Collett, Jason A; Corridon, Peter R; Mehrotra, Purvi et al. (2017) Hydrodynamic Isotonic Fluid Delivery Ameliorates Moderate-to-Severe Ischemia-Reperfusion Injury in Rat Kidneys. J Am Soc Nephrol 28:2081-2092
Mehrotra, Purvi; Collett, Jason A; McKinney, Seth D et al. (2017) IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats. Am J Physiol Renal Physiol 312:F385-F397
Basile, D P; Collett, J A; Yoder, M C (2017) Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury. Acta Physiol (Oxf) :
de Bragan├ža, Ana C; Volpini, Rildo A; Mehrotra, Purvi et al. (2016) Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury. Physiol Rep 4:
Basile, David P; Bonventre, Joseph V; Mehta, Ravindra et al. (2016) Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments. J Am Soc Nephrol 27:687-97
Mehrotra, Purvi; Patel, Jaymin B; Ivancic, Carlie M et al. (2015) Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism. Kidney Int 88:776-84
Basile, David P; Yoder, Mervin C (2014) Renal endothelial dysfunction in acute kidney ischemia reperfusion injury. Cardiovasc Hematol Disord Drug Targets 14:3-14
Basile, David P; Yoder, Mervin C (2014) Circulating and tissue resident endothelial progenitor cells. J Cell Physiol 229:10-6
Basile, David P; Dwinell, Melinda R; Wang, Shur-Jen et al. (2013) Chromosome substitution modulates resistance to ischemia reperfusion injury in Brown Norway rats. Kidney Int 83:242-50

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